The present invention relates, in general, to a method of producing a therapeutic effect and, in particular, to a method of using antibodies to promote cellular function, to antibodies suitable for use in such a method and to compositions comprising same.
To date, the use of immunoglobulins for therapy has been guided by the premise that antibodies neutralize antigens and block function or that antibodies can kill cells. The use of immunoglobulins for such purposes is well grounded in practice and research. Immunological therapies have been used to treat malignant tumors (Miller et al, New Eng. J. Med. 9:517 (1982)), to reduce allograft rejection (Bluestone et al, Immunol. Rev. 90:5 (1986)), and to prepare vaccines against viral infections (Finberg and Ertl, Immunol. Rev. 90:129 (1986)). The feasibility of using antibodies as therapeutics has been greatly improved by the development of technology to humanize rodent monoclonal antibodies and thereby render them non-immunogenic in humans (Hardman et al, J. Biol. Markers 7:203 (1992); Carter et al, Proc. Natl. Acad. Sci. USA 89:4285 (1992); Routledge et al, Eur. J. Immunol. 21:2717 (1991); Gussow and Seemann Meth. Enzyme 203:99 (1991)). Although humanized antibodies have certain side effects, such effects can generally be kept at therapeutically acceptable levels.
In contrast to the traditional use of immunoglobulins as agents to inhibit or neutralize function, the present invention is based on the realization that immunoglobulins can also be used as agonists to facilitate function. Neugebauer et al (Nature 350:68 (1991) disclose anantibody that promotes adhesion but no reference is made to inducing cell signalling or facilitating a cellular function, such as motility). Antibodies suitable for use in the present invention, designated xe2x80x9cagonist antibodiesxe2x80x9d, include those that are mirror images of a particular epitope. One method of generating such antibodies involves the manipulation of the immune system so as to prevent the normal suppression of the system that is responsible for preventing auto-immunity (Matthew and Sandrock, J. Immunol. Methods 100:73 (1987)). The immune system can thus be permitted to produce idiotypic antibodies that are directed to the original antigen and anti-idiotypic antibodies that are directed to the newly circulating antibodies (Jerne, Ann. Immunol. 125C:373 (1974); Matthew, Soc. for Neurosci. Short Course, Anaheim, Calif. (1992)). Anti-idiotypic antibodies can thereby be produced that mimic molecules (e.g. growth factors) that interact with cell surface receptors. In accordance with the present invention, such antibodies can be used as therapeutics to replace or supplement biologically active molecules in facilitating biological function.
It is a general object of the invention to provide antibodies that promote cellular functions such as survival, growth and motility.
It is a specific object of the invention to provide antibodies that mimic molecules that interact with cell surface receptors and thereby facilitate cellular functions.
It is another object of the invention to provide antibodies for use in promoting neuronal cell growth and glial migration.
It is a further object of the invention to provide methods of treating injuries and diseases, particularly those of the peripheral and central nervous system.
In one embodiment, the present invention relates to a method of facilitating a biological function of a cell. The method comprises contacting the cell with an antibody, or binding fragment thereof, that mimics an agent that binds to a receptor on the surface of the cell and thereby facilitates the function. The contacting is effected under conditions such that the antibody binds to the receptor and thereby facilitates the function.
In another embodiment, the present invention relates to a method of stimulating migration of a Schwann cell. The method comprises contacting the cell with an antibody, or binding fragment thereof, that binds to a receptor on the surface of the cell that regulates migration of the cell. The contacting is effected under conditions such that the antibody binds to the receptor so that migration is thereby stimulated.
In a further embodiment, the present invention relates to a method of treating a de-myelinating disease. The method comprises administering to a patient in need thereof an antibody, or binding fragment thereof, that binds to a receptor on the surface of Schwann cells of the patient that regulates migration of the Schwann cells. The amount administered is sufficient to stimulate migration of the Schwann cells.
In yet another embodiment, the present invention relates to a method of regulating calcium homeostasis of a mammal in need thereof. The method comprises administering to the mammal an amount of a GM1 anti-idiotypic antibody sufficient to effect the regulation.
In further embodiments, the present invention relates to an isolated GM1 anti-idiotypic antibody and an isolated antibody specific for a Schwann cell surface antigen that potentiates Schwann cell migration.
In yet another, embodiment, the present invention relates to a method of protecting a mammalian cell from a toxic effect of a free radical. The method comprises contacting the cell with an anti-idiotypic GM1 antibody under conditions such that the protection is effected.
Further objects and advantages of the present invention will be clear from the Description that follows.